Cancer cachexia, often referred to as cancer anorexia-cachexia syndrome (CACS), is a multifactorial condition with a high prevalence in non-small cell lung cancer (NSCLC). Cancer cachexia is characterized by decreased body weight (mainly lean body mass; LBM), and is associated with worsened morbidity and survival. Standard effective treatments are lacking, although anamorelin has shown promise as a treatment in this field. Anamorelin is a novel, selective ghrelin receptor agonist with appetite-enhancing and anabolic activity.
A standard off-label therapy for cancer cachexia is megestrol acetate, which is approved to increase appetite and prevent weight loss in patients with AIDS. However, megestrol has only been shown to increase body weight and water in patients, and does not improve fat mass or lean body mass.
Megestrol acetate also has not been shown to improve quality of life in cancer cachexia patients. Lesniak et al. conducted a systematic review of clinical trials with megestrol acetate, and reported: “Based on a systematic review of trials with megesterol acetate in patients with cancer anorexia-cachexia syndrome, quality of life was measured using different scales in 14 studies, and in 13 of the 14 studies, there was no significant difference between patients receiving megesterol acetate and those taking placebo, dronabinol, eicosapentaenoic acid or glucocorticosteroids.” Leśniak W1, Bala M, Jaeschke R, Krzakowski M., Effects of megestrol acetate in patients with cancer anorexia-cachexia syndrome—a systematic review and meta-analysis. Pol Arch Med Wewn. 2008 November; 118(11):636-44.
Other drugs have also failed to improve the quality of life in cancer cachexia patients. Del Fabbro reported a double-blind placebo-controlled trial and the effect of melatonin on appetite and other symptoms in patients with advanced cancer and cachexia. No differences between melatonin and placebo groups after 4 weeks were observed regarding weight, body composition (including fat-free mass), symptom scores, and quality-of-life outcomes (as measured by FACIT-F and FAACT). Del Fabbro E1, Dev R, Hui D, Palmer L, Bruera E. Effects of melatonin on appetite and other symptoms in patients with advanced cancer and cachexia: a double-blind placebo-controlled trial. J Clin Oncol. 2013 April 1; 31(10):1271-6.
Enobosarm ((2S)-3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide) (also known as Ostarine, GTx-024 and MK-2866) is an investigational selective androgen receptor modulator (SARM) under development for conditions such as muscle wasting and osteoporosis. Dobs et al. report phase 2 data that includes some quality of life data as measured by FAACT/FACIT-F, but it only compares the measurements to baseline within treatment arms rather than assessing active versus placebo, rendering any conclusions difficult to reach. Dobs A S et al., Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Dobs A S et al., www.thelancet.com/oncology Published online Mar. 14, 2013 http://dx.doi.org/10.1016/S1470-2045(13)70055-X.
Garcia and Polvino performed a Phase I study (single-center, randomized, double-blind, and placebo-controlled) in which healthy subjects were divided into three dosage groups. Garcia, J. M., Polvino, W. J. Effect on body weight and safety of RC-1291, a novel, orally available ghrelin mimetic and growth hormone secretagogue: results of a phase I, randomized, placebo-controlled, multiple-dose study in healthy volunteers, Oncologist, 2007; 12:594-500. The first group received placebo or 25 mg anamorelin once per day, for 5 days. The second group received anamorelin at either 25 mg twice per day or 50 mg once per day for 6 days, and then crossed over to the other dosage regimen for 5 days; three subjects in this group received placebo for all 11 doses to maintain double-blinding. The third group received placebo or 75 mg anamorelin once per day for 6 days. Subjects who received anamorelin at either 50 or 75 mg doses had significant dose-related weight gain after 6 days versus placebo, with the greatest increases seen with daily dosing. The mean increase in body weight from baseline after 50 mg (once daily dose or split-dose regimen) or 75 mg anamorelin once per day was significant relative to placebo.
A follow-up study by Garcia and Polvino characterized the effects of anamorelin on growth hormone (GH) levels in healthy subjects, as well as its effects on insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), serum hormone profiles, and carbohydrate metabolism. Garcia, J. M., Polvino, W. J. Pharmacodynamic hormonal effects of anamorelin, a novel oral ghrelin mimetic and growth hormone secretagogue in healthy volunteers, Growth Horm IGF Res, 2009; 19:267-73. This study (single-center, randomized, double-blind, and placebo-controlled) used the same dosage groups as the previous study (i.e., one group received placebo or a single dose of 25 mg anamorelin once per day, the second group received placebo or either 25 mg anamorelin twice per day or 50 mg anamorelin once per day for 6 days, and then switched to the other dosage regimen for 5 days, and the third group received placebo or 75 mg anamorelin once per day). All doses of anamorelin significantly increased GH and IGF-1 levels, particularly the 50 mg single dose and 75 mg dose; the split 50 mg dose showed an increase in GH and IGF-1 levels, but not to the same degree as the single 50 mg dose. Again, significant increases in body weight were seen in groups receiving the 50 mg dose (single or split dose) and 75 mg dose. Increases in body weight correlated strongly with increases in IGF-1 levels.
Garcia et al then performed a pilot study (multicenter, randomized, double-blind, placebo-controlled, crossover study) of anamorelin treatment in patients with various cancers and cachexia who had an involuntary body weight loss of over 5% in the previous 6 months, an estimated life expectancy of over 3 months, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Garcia, J. M., Friend, J., Allen, S. Therapeutic potential of anamorelin, a novel, oral ghrelin mimetic, in patients with cancer-related cachexia: a multicenter, randomized, double-blind, crossover, pilot study, Support Care Cancer, 2013; 21:129-37. A single dose of 50 mg anamorelin or placebo was given once per day over the course of the study, followed by a 3 to 7-day washout period, and then treatments were switched. Study assessments included body weight, appetite, food intake, growth hormone (GH) levels, and patient-reported symptom assessment (as measured by the Anderson Symptom Assessment Scale (ASAS), the Functional Assessment of Chronic Illness Therapy With Additional Fatigue Domain (FACIT-F), and the Bristol-Myers Anorexia/Cachexia Recovery Instrument, 7-question version (BACRI-7)). Anamorelin significantly increased body weight compared with placebo. GH, IGF-1, and IGFBP-3 levels also significantly increased with anamorelin, particularly in terms of the mean serum concentrations of the hormones. Food intake increased but not significantly. Patient-reported appetite significantly improved with anamorelin as measured by ASAS; as measured by BACRI-7, there was no significant difference in appetite among treatment groups although significantly more patients reported greater enjoyment from eating while on anamorelin therapy. Anamorelin treatment also significantly increased FACIT-F scores.
Garcia et al performed a phase II trial (multicenter, randomized, double-blind, and placebo-controlled) lasting 12 weeks and including 81 patients with various cancers with cachexia (body weight loss of over 5% within the previous 6 months), and an ECOG score of 0-2. Garcia, J., Boccia, R. V., Graham, C., Kumor, K., Polvino, W. A phase II randomized, placebo-controlled, double-blind study of the efficacy and safety of RC-1291 (RC) for the treatment of cancer cachexia, J Clin Oncol, 2007; 25:18(S):9133. Patients received either 50 mg anamorelin once per day or placebo during the 12-week study, and quality of life (FACIT-F), weight gain, IGF-1 and IGFBP-3 were measured over the course of the trial. Total and lean body mass significantly increased as compared to placebo at weeks 4 and 8; the magnitude of the increase was stable from weeks 4 to 12 for both total and lean body mass. Fat mass decreased more in placebo-treated patients than in anamorelin-treated patients, although the difference did not reach statistical significance. See WO/2008/124183 of Mann and Polvino. Interestingly, no corresponding increase in scale weight measures was noted. Levels of IGF-1 and IGFBP-3 were significantly increased at weeks 4, 8, and 12. No significant effects on quality of life as measured by the FACIT-F test were noted. However, ASAS scores were improved. See WO/2008/124183 of Mann and Polvino.
Temel et al conducted a phase II study (multicenter, randomized, double-blind, and placebo-controlled) lasting 12 weeks in 226 patients with advanced non-small cell lung cancer (NSCLC) and an ECOG score 0-1 who were candidates for treatment with carboplatin/paclitaxel (with or without bevacizumab). Temel J. B., S; Jain, M et al. Efficacy and safety of anamorelin HCl in NSCLC patients: results from a randomized, double-blind, placebo-controlled, multicenter phase II study, Presented at the European Cancer Congress, 27 Sep.-1 Oct. 2013, Amsterdam, Netherlands; Abstract no 1308. Patients were given once daily doses of 50 or 100 mg anamorelin or matching placebo, and weight gain and IGFBP-3 levels were measured over the course of the study. The group receiving 100 mg anamorelin had a statistically significant average weight gain from baseline to week 12. Anamorelin therapy led to statistically significant increases in IGFBP-3 as compared to placebo. Anamorelin also improved patient scores on the MD Anderson Symptom Inventory (MDASI), which measures the severity of symptoms on daily functioning among cancer patients, although the improvement was not significant.
A Study of anamorelin in NSCLC, presented at ASCO Quality Care 2013, included results of individual MDASI questions, including the response on fatigue. This study was only in NSCLC patients, not in NSCLC patients suffering from cachexia. http://meetinglibrary.asco.org/content/119980-140
U.S. Pat. No. 6,303,620 discloses the use of novel compounds including anamorelin for: reducing cachexia due to cancer; treating anorexia; regulating food intake; improving muscle strength; treating chronic or acute fatigue syndrome and insulin resistance; treating conditions which require increased plasma GH levels; treating immunosuppressed patients; and treating cardiomyopathy, cardiac failure, impaired cardiac function, and myocardial infarction.
U.S. Pat. No. 7,994,329 discloses the use of agonists of growth hormone secretagogue receptor type 1A (GHSR 1A) for use in medicaments for the regulation of food intake, body mass index (BMI), and the treatment of anorexia, type II diabetes and wasting associated with various diseases and conditions.
U.S. Pat. No. 8,394,833 discloses the use of anamorelin for reducing nausea, treating emesis and also evaluated quality of life as measured by the ASAS (rating of the severity from 1-10 of the following symptoms: pain, fatigue, nausea, depression, anxiety, drowsiness, shortness of breath, appetite, sleep and feeling of well-being) and the use of growth hormone secretagogues for increasing appetite and body weight and IGF-1 levels.
U.S. Pub. No. 2005/0261201 discloses the use of a growth hormone secretagogue for reducing C-reactive protein in a patient suffering from cachexia, anorexia, chronic fatigue syndrome, diabetes, and tumor metastasis as well as inducing secretion of GH and IGF-1, and its use in treating a patient who has had or who is at risk of a vascular event such as myocardial infarction.
WO/2013/158874 discloses the use of anamorelin HCl for the treatment of cancer-related cachexia and conditions which require increased plasma GH levels, and the use of growth hormone secretagogues for increasing appetite and body weight.
None of these patent publications discloses the use of anamorelin to treat early satiety or fatigue resulting from cachexia, or for increasing survival time of terminally ill cancer patients. They also do not disclose improvement of patient quality of life as measured by the anorexia/cachexia domain of the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) assessment, which measures physical and functional well-being as well as specific concerns related to anorexia and cachexia by asking questions directed to body weight/image, appetite, food consumption, vomiting, early satiety, and stomach pain.